Aberrant expression of erythropoietin in uterine leiomyoma: implications in tumor growth

• Published in: American journal of obstetrics and gynecology Vol. 213; no. 2; pp. 199.e1 - 199.e8
• Main Authors: Asano, Ryoko, MD, Asai-Sato, Mikiko, MD, PhD, Miyagi, Yohei, MD, PhD, Mizushima, Taichi, MD, Koyama-Sato, Makiko, MD, PhD, Nagashima, Yoji, MD, PhD, Taguri, Masataka, PhD, Sakakibara, Hideya, MD, PhD, Hirahara, Fumiki, MD, PhD, Miyagi, Etsuko, MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2015
• Subjects: Adult; Aged; Antigens, CD34 - metabolism; Blood Vessels - metabolism; Blood Vessels - pathology; Enzyme-Linked Immunosorbent Assay; erythropoietin; Erythropoietin - genetics; Erythropoietin - metabolism; Female; Humans; Immunohistochemistry; Leiomyoma - blood supply; Leiomyoma - genetics; Leiomyoma - metabolism; Middle Aged; myomatous erythrocytosis syndrome; Myometrium - metabolism; Obstetrics and Gynecology; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; uterine leiomyoma; Uterine Neoplasms - blood supply; Uterine Neoplasms - genetics; Uterine Neoplasms - metabolism; vessel maturity; uterine leiomyoma; vessel maturity; myomatous erythrocytosis syndrome; erythropoietin
• ISSN: 0002-9378; 1097-6868
• DOI: 10.1016/j.ajog.2015.02.016

Objective Myomatous erythrocytosis syndrome is a rare complication of uterine leiomyoma caused by erythropoietin (EPO) that is produced by tumor cells. We assessed the EPO expression in leiomyomas and investigated the effects of EPO on the tumor growth. Study Design Tissue samples were collected from 114 patients with uterine leiomyomas who underwent myomectomy or hysterectomy in Yokohama City University Hospital. From 17 patients, the corresponding normal myometrium was also collected. All samples were analyzed for EPO messenger RNA (mRNA) expression by real-time reverse transcription-polymerase chain reaction. EPO protein expression was determined by an enzyme-linked immunosorbent assay. The relationships between EPO expression and clinicopathological features were retrospectively analyzed using the patients’ charts. Blood vessel density and maturity were assessed using hematoxylin-eosin staining and CD34 immunohistochemistry. Results EPO mRNA expression was detected in 108 of 114, or 95%, of the leiomyomas. The mean EPO mRNA expression in the leiomyoma was higher than the corresponding normal myometrium (3836 ± 4122 vs 1455 ± 2141; P  = .025 by Wilcoxon rank test). The EPO mRNA expression in the leiomyomas varied extensively among samples, ranging from undetectable levels to 18-fold above the mean EPO mRNA of normal myometrium. EPO protein production was observed concomitant with mRNA expression. A positive correlation of leiomyoma size and EPO mRNA expression was shown by Spearman rank correlation coefficient (ρ = 0.294; P  = .001), suggesting the involvement of EPO in leiomyoma growth. The blood vessel maturity was also significantly increased in EPO-producing leiomyomas (high vessel maturity in high vs low EPO group: 67% vs 20%; P  = .013 by Fisher exact test). Conclusion This report demonstrates that EPO is produced in most of conventional leiomyomas and supports a model in which EPO accelerates tumor growth, possibly by inducing vessel maturity. Our study suggests one possible mechanism by which some uterine leiomyomas reach a large size, and the understanding of EPO expression patterns in these tumors may be useful for management of the patients with leiomyomas.